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Letter to Hospitals Regarding Abbokinase

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Contact
BGTD

Therapeutic Products Programme
Tunney's Pasture
Address Locator # 0603D
OTTAWA, Ontario
K1A 0L2

July 23, 1999

Dear Sir/Madam:

The Therapeutic Products Programme (TPP) of Health Canada wishes to provide the following updated information regarding Abbokinase (Urokinase for Injection).

As indicated in our previous correspondence of February 4, and March 24, 1999, Current Good Manufacturing Practices (CGMP) deficiencies were identified last fall during inspections by the US FDA, of Abbott Laboratories and of its supplier of the human neonatal kidney cells used to manufacture Abbokinase. As a result of the additional in-process testing mandated by the FDA, three unfinished lots of in-process material which were not manufactured into finished Abbokinase or distributed, were found to contain reovirus.

The FDA has now obtained additional information regarding the inadequacy of the screening and testing of the mothers and donors of the human kidney cells used to produce Abbokinase. Information was also obtained regarding seven instances of in-process lots of product being contaminated with reovirus and mycoplasma.

Over the past several months, Abbott has informed FDA of additional in-process lots of Abbokinase contaminated with microorganisms. In total, six such lots were found to contain various strains of reovirus, a virus that usually results in no symptoms or causes minor respiratory or gastrointestinal symptoms. Another in-process lot was contaminated with mycoplasma, a microorganism that can cause respiratory infections, and, on rare occasions, other infections that may be serious. Abbott has assured FDA that none of these in-process lots were manufactured into final product or distributed.

These recent findings of contamination and the inability to locate the source of the problem have resulted in further concerns about Abbott's manufacturing process for Abbokinase. Abbott's deviations from CGMP could significantly impact the safety of the product. Particularly, deficiencies in manufacturing practices could also lead to the product being contaminated with microorganisms that have not yet been detected.

In its most recent letter to Abbott, the FDA has detailed the steps Abbott needs to take to correct the serious and significant manufacturing deviations before Abbott will be allowed to distribute new lots of Abbokinase. These include:

• completing a thorough and adequate investigation of the reovirus and mycoplasma contamination, including the source of the contamination;
• manufacturing Abbokinase using human kidney cells that have been obtained, processed, and tested through adequate methods, and;
• assuring that fully validated methods are used in the manufacturing process to test for infectious agents and remove them.

Abbott has initiated validation studies for the process of removal or inactivation of infectious agents during the manufacturing process, but these studies have not yet been completed.

In our February 4, 1999, letter it was announced that due to the FDA actions, Abbokinase would be available in Canada only via the Special Access Programme. TPP is to date not aware of any cases of infectious diseases that can be attributed to the use of Abbokinase. However, due to the possibility that cases of infectious diseases caused by Abbokinase may not have been recognized as such and reported to TPP, the actual risk to patients of developing an infectious disease as a result of using Abbokinase is unknown.

Abbokinase will remain available in Canada only via the Special Access Programme. The lots currently being distributed in Canada are those which have undergone additional testing and have been found to be free of contaminating microorganisms. Practitioners should be aware that the supply of these lots is limited and in the near future Abbokinase may no longer be available. Therefore, for each situation in which the use of Abbokinase is being contemplated, we encourage physicians to consider the appropriateness of other treatment options.

Yours sincerely,

(original signed by D. Krepps for)

K. Bailey, D.Phil.
Director
Bureau of Biologics and Radiopharmaceuticals
Tel: (613) 957-8064
Fax: (613) 957-6302
E-mail: keith_bailey@hc-sc.gc.ca